Thermal therapy consists of raising the temperature of living tissues until they are destroyed. This type of treatment can be divided into two main groups: hyperthermia in which the temperatures reach 46° C. and thermal ablation in which the temperature exceeds 47° C. Thermal therapy, and in particular hyperthermia, have been used to intensify radio- and chemotherapy treatments; tumorous tissues are more sensitive to heat than healthy tissues and additionally the temperature increase sensitises the cancer cells to chemotherapy and radiation treatments. In experimental and clinical oncology, hyperthermia treatments have already been used to raise the temperature of tumorous areas to 42-46° C.
Another possible application of hyperthermia in the field of biomedicine consists of controlling the aggregation of proteins which form deposits in the tissues called amyloids. If they accumulate in sufficient quantity, these deposits can alter the normal functioning of the tissue. Amyloidosis is involved in diseases such as diabetes mellitus, tuberculosis and rheumatoid arthritis, and there is also evidence linking amyloidosis with neurodegenerative diseases such as Alzheimer's and Parkinson's diseases.
Magnetic nanoparticles have been used in the diagnosis and monitoring of the growth of tumours. These particles, due to their magnetic properties, have served greatly to improve the contrast in nuclear magnetic resonance images. Another field in which nanoparticles have been used is in the controlled release of drugs, concentrating them in the affected area by the use of magnetic fields.
Currently, there are various microwave hyperthermia devices used for the treatment of tumorous tissues. These devices do not use nanoparticles and instead directly irradiate the diseased tissues with a microwave field which has destructive effects at a local level. This method is known by the name of interstitial hyperthermia.
Interstitial hyperthermia systems are rather aggressive towards the subject since, for maximum control of the irradiated area, antennas have to be implanted in the tissues by surgical methods, for example by means of a catheter (see U.S. Pat. No. 6,097,985), or by the insertion of an active radio-frequency electrode in the tumorous tissue which releases the energy of the electromagnetic field (see U.S. Pat. No. 5,507,743).
As an alternative to these aggressive techniques, several hyperthermia treatments have been proposed which are based on the use of magnetic fluids as a medium for dissipating the heat in living tissues. These fluids are made up of biocompatible magnetic fine particles or nanoparticles which are stabilized to prevent them from forming aggregates.
This type of procedure has the advantage that it does not involve the surgical implantation of antennas or electrodes in the diseased tissues, rather it uses magnetic fluids such as, for example, nanoparticles formed from magnetite (R. Hergt, W. Andrä, C. G. d'Ambly, I. Hilger, W. A. Kaiser, U. Richter, H-G. Schmidt, IEEE Trans. Mag. 34 (1998) 3745), a material having an acceptable biocompatibility, making it an ideal candidate for the preparation of magnetic fluids. In this case, the mechanisms for dissipation of the energy in the form of heat are mainly related to losses due to hysteresis and losses due to relaxation and friction, there being no losses due to induced Foucault currents. Each of these phenomena is discussed further below.
Losses due to hysteresis: Hysteresis is the tendency of a material to retain one of its properties, in this case magnetization (M), in the absence of the stimulus which has produced a change in that property, in this case an external magnetic field (H). In other words, if an external magnetic field is applied to a magnetic material, its magnetization will grow if the field increases to a maximum value (Hmax). If the field is then decreased, the magnetization will not decrease as quickly as it increased. By representing the values of the external magnetic field compared to the magnetization, it can be seen that the relation between M and H not only is non-linear, it is not single-valued either. If the field is reduced to a minimum value (Hmin=−Hmax) and then the direction of the field is changed to make it increase again to Hmax, the curve M against H turns out to be a closed curve known as a hysteresis curve or cycle (represented in FIG. 1). In all systems with hysteresis, there is an irreversible conversion of energy (or work) into heat throughout a complete cycle. In this case, it involves a conversion of magnetic energy into heat; this heat is equal to the area enclosed by the hysteresis curve.
Losses due to induced Foucault currents: When an electric conductor is in a time variable magnetic field (B(t)), the magnetic flux (F(t)) which passes through the conductor will also be variable with time. This variation in time induces a current in the conductor, the direction of which opposes the variation of the magnetic flux. The induced current has its origin in a generated electric field which produces a movement of free charges in the metal conductor, ultimately generating currents which, as a result of the Joule effect, will dissipate energy in the form of heat.
Losses due to relaxation and friction: In magnetic materials, domains with different orientations of the magnetic moment (m) are formed. In the grain boundaries of these domains, it can be considered that there are two metastable states of m, and corresponding to each state is an energy level, the difference corresponding with the anisotropy energy of the system (Eanis). In the presence of an external magnetic field (H), there is a probability of transition from one state to the other, which will give rise to a loss of energy in the form of heat, this mechanism also being known as relaxation due to the Néel effect. In the case of ferrofluids with a viscosity index, relaxation may also occur due to rotational Brownian movements of the magnetic particles, a very important phenomenon when the direction of the magnetic moment is strongly coupled to the particle and the movements due to the relaxation of m produce friction of the nanoparticles with the surrounding medium and/or other nanoparticles.
The magnetic properties of nanoparticles substantially depend on their size and structure. Ferromagnetic fluids have been investigated in respect of radio-frequency-induced hyperthermia in cells in vitro (N. A. Brusentsov, V. V. Gogosov, T. N. Brusentsova, A. V. Sergeev, N. Y. Jurchenko, A. A. Kuznetsov, O. A. Kutnetsov, L. I. Shumakov, J. Magn. Magn. Mater. 225 (2001) 113) and in solid tumours in human beings (A. Jordan, R. Scholz, K. Maier-Hauff, M. Johannsen, P. Wust, J. Nadobny, H. Schirra, H. Schmidt, S. Deger, S. Loening, W. Lanksch, R. Felix, J. Magn. Magn. Mater. 225 (2001) 118).
Unfortunately, control of the temperature in the area of a tumour has so far proved to be very complicated to achieve. There is the risk of that overheating occurs, leading to healthy tissues being damaged as well. In order to solve this problem, recent attempts have been made to develop a different type of magnetic nanoparticle with a Curie temperature (i.e., the temperature above which a ferromagnetic body loses its magnetism, behaving in the same way as a purely paramagnetic material) of between 40 and 46° C. for possible application in medical hyperthermia treatments (Y. Haik, C-J. Chen, US Publication No. 2005/0249817). However, the effects on living organisms of the radio-frequency field necessary for producing a significant change in temperature are still not fully known. In addition, the materials used in nanoparticles with a controlled Curie temperature are transition metals, such as for example: nickel, copper, chromium, gadolinium, cobalt, manganese and zinc which are highly toxic to living creatures.
On the other hand, there are indirect observations in respect of the heating of metal gold nanoparticles under the action of an alternating electromagnetic field (K. Hamad-Schifferli, J. J. Schwartz, A. T. Santos, S. Zhang, J. M. Jacobson, Nature 415 (2002) 152; M. J. Kogan, N. G. Bastus, R. Amigo, D. Grillo-Bosch, E. Araya, A. Turiel, A. Labarta, E. Giralt, V. F. Puentes, Nanoletters 6 (2006) 110). The structural change of proteins or dehybridization of DNA chains bound to metal gold nanoparticles has been attributed to the dissipation of heat due to the Joule effect of the Foucault currents induced in the nanoparticles by the application of an electromagnetic field. The dissipation of heat, with the consequent rise in temperature of the medium, has always been determined in these systems from indirect observations related to the change in structure of the compounds with which the nanoparticles combine. Therefore, an exact and precise control of the temperature reached is not achieved, since it is only possible to estimate it indirectly.
In the field of the controlled release of drugs, hyperthermia has been proposed for use in drug dosing. There are studies relating to the release of drugs from liposomes (A. M. Ponce, B. L. Viglianti, D. Yu, P. S. Yarmolenko, C. R. Michelich, J. Woo, M. B. Bally, M. W. Dewhirst, J. Natl. Cancer Inst. 99 (2007) 53), which demonstrate that the dosing of the drugs is much more homogeneous and effective than by conventional methods. However, the application of the electromagnetic field as carried out until now in these systems involves the use of excessively aggressive techniques such as the surgical implantation of a microwave antenna for irradiating the affected area and inducing release of the drug.
Furthermore, in many cases, there are drugs which cannot pass through the biological barriers of living organisms, for example the cellular membrane or the haematoencephalic barrier; however such drugs could perform very important therapeutic functions within the cell or cerebrum. Nanoparticles bound to said drugs with a biocompatible coating are capable of passing through the aforementioned biological barriers; once through the barrier and with application of a radio-frequency field, the biocompatible coating changes its structure as a result of the rise in temperature, releasing the drug in the desired place.
Accordingly, there remains a problem in the art in employing hyperthermia in applications where it is necessary to heat a specific area in a controlled way.